title: Safety, effectiveness, and cost of dipeptidyl peptidase-4 inhibitors versus intermediate acting insulin for type 2 diabetes: protocol for a systematic review and network meta-analysis.
abstract: BACKGROUND
  Type 2 diabetes mellitus (T2DM) results from insulin resistance and relative insulin deficiency. T2DM treatment is a step-wise approach beginning with lifestyle modifications (for example, diet, exercise), followed by the addition of oral hypoglycemic agents (for example, metformin). Patients who do not respond to first-line therapy are offered second-line therapy (for example, sulfonylureas). Third-line therapy may include insulin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors.It is unclear whether DPP-4 inhibitors are safer and more effective than intermediate acting insulin for third-line management of T2DM. As such, our objective is to evaluate the comparative effectiveness, safety and cost-effectiveness of DPP-4 inhibitors versus intermediate acting insulin for T2DM patients who have failed both first- and second-line diabetes treatments.
  
  
  METHODS
  Electronic searches of MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and grey literature (for example, trial registries, public health websites) will be conducted to identify studies examining DPP-4 inhibitors compared with each other, intermediate acting insulin, no treatment, or placebo for adults with T2DM. The outcomes of interest include glycosylated hemoglobin (A1C) (primary outcome), as well as emergency department visits, physician visits, hospital admissions, weight gain, quality of life, microvascular complications, macrovascular complications, all-cause mortality, and cost (secondary outcomes). Randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort studies, and cost studies reporting data on these outcomes will be included. Eligibility will not be restricted by publication status, language of dissemination, duration of study follow-up, or time period of study conduct.Two reviewers will screen the titles and abstracts resulting from the literature search, as well as potentially relevant full-text articles, in duplicate. Data will be abstracted and quality will be appraised by two team members independently. Conflicts at all levels of screening and abstraction will be resolved through team discussion.Our results will be described narratively. Random effects meta-analysis and network meta-analysis will be conducted, if feasible and appropriate.
  
  
  CONCLUSIONS
  Our systematic review results can be used to determine the most effective, safe and cost-effective third-line strategies for managing T2DM. This information will be of great use to health policy-makers and clinicians, as well as patients living with T2DM and their families.
  
  
  BACKGROUND
  PROSPERO registry number: CRD42013003624.
authors.affiliation: Li Ka Shing Knowledge Institute, St, Michael's Hospital, 209 Victoria Street, East Building, Toronto, Ontario M5B 1T8, Canada.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Tricco
authors.forename: Jesmin
authors.initials: J
authors.lastname: Antony
authors.forename: Charlene
authors.initials: C
authors.lastname: Soobiah
authors.forename: Brenda
authors.initials: B
authors.lastname: Hemmelgarn
authors.forename: David
authors.initials: D
authors.lastname: Moher
authors.forename: Brian
authors.initials: B
authors.lastname: Hutton
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Yu
authors.forename: Sumit R
authors.initials: SR
authors.lastname: Majumdar
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Straus
mesh_terms: D003362:Cost-Benefit Analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D007328:Insulin / Q000009:adverse effects / Q000627:therapeutic use*; D015201:Meta-Analysis as Topic; D017063:Outcome Assessment, Health Care; D012107:Research Design; D012449:Safety; D000078202:Systematic Reviews as Topic
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin